This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, and NCT00001322. The menopause transition is accompanied by a decrease in quality of life (QOL) measures for some women, and several randomized controlled trials of menopausal hormone therapy (HT) have targeted QOL as a potential indication for HT. We have characterized the impact of Perimenopausal depression (PMD) on QOL, disability, social adjustment and role functioning. Our findings show that PMD is accompanied by a decreased QOL, decreased social adjustment and impaired role functioning comparable to depression and anxiety disorders occurring at other stages of a womans life. Neither perimenopausal reproductive status alone nor the presence of hot-flushes had a significant negative impact on QOL measures. Nonetheless, it remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for depression during the perimenopause or the effects of a current depression. The latter question was recently clarified by the results of our longitudinal study of women as they transition through the perimenopause. Specifically, we examined whether the changes in negative life events and declines in QOL measures observed in cross-sectional studies were antecedents of PMD or reflect the effects of the presence of depression. Thus, we prospectively evaluated healthy women longitudinally across the menopause transition. Seventy asymptomatic, premenopausal women, ages 41-55 years, were monitored longitudinally for an average of 5.2 years until 6-12 months after their final menses (FMP). Outcome measures included the Structured Clinical Interview for DSM-IV (SCID), as well as standardized measures of QOL, marital satisfaction, and life events. Twenty-eight episodes of major and minor depression occurred in twenty-two women, twenty-seven of these episodes occurred in the 2-years surrounding the FMP. Thus confirming reports by our group and others of the clustering of depressions during the late menopause transition a time associated with declining levels of ovarian estradiol secretion. During the four years prior to the FMP, compared to women who remained asymptomatic, women with PMD reported significantly lower life satisfaction in PMD but did not report significant differences in overall QOL, marital satisfaction, experience of personal loss, or negative life events. Thus, these data suggest that negative life events and decreased QOL/marital dissatisfaction do not uniformly precede the onset of PMD. Further, the relative absence of antecedent social or environmental in PMD suggests a more specific role for hormonal events in the triggering of PMD. A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiols antidepressant efficacy in PMD. Additionally, we have completed a subsequent placebo-controlled study examining the effects on mood and behavior in women with PMD of estradiol and two compounds: the selective estrogen receptor (ER) modulator (SERM), raloxifene and a phytoestrogen (plant-derived estrogen-like compounds). In this study we replicated our previous findings that estradiol therapy is effective in the treatment of PMD; however, neither raloxifene nor the phytoestrogen showed significant effects on symptoms in PMD. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In our studies of the effects of estradiol withdrawal on mood, we first examined the effects of inducing estradiol withdrawal and hypogonadism on mood symptoms in asymptomatic premenopausal women participating in our gonadotropin-releasing hormone (GnRH) agonist protocol. We observed only four women (5.6% of the sample) who reported Beck Depression Inventory (BDI) scores > 10 (suggestive of clinically significant symptoms of depression), and in only one of these women did the elevated BDI scores persist beyond two weeks duration. Neither plasma estradiol levels nor the severity of hot flushes correlated with mood rating scores. Thus, in otherwise healthy women the induction of neither hypogonadism nor hot flushes (with an accompanying sleep disturbance) uniformly precipitates depressive symptoms. These data, and the results of epidemiologic data confirming that the majority of women do not develop depression during the menopause transition, led to our examining whether women with a past PMD are differentially sensitive to the effects of estradiol withdrawal. We next evaluated the effects of the acute withdrawal of estradiol therapy in women with and those without a past PMD. In this study, asymptomatic postmenopausal women who experienced a depression during the menopause transition and asymptomatic postmenopausal women with no past depression received a standard dose of estradiol (100 mcg per day). After three weeks all women were randomly assigned under double-blind (DB) conditions to either continue estradiol (DB ET) or switch to placebo (DB placebo, estradiol withdrawal). If estradiol withdrawal was a relevant physiologic event to trigger depression, then one would predict that depressive symptoms would develop in those women randomized to placebo. Additionally, if women who develop depression during the perimenopause are differentially susceptible to the mood destabilizing effects of estradiol withdrawal, then mood symptoms should emerge in the women with past PMD but not the controls randomized to DB placebo. Results demonstrate that estradiol withdrawal induces depressive symptoms in women with past PMD (n = 26), but not in those without such a history (n = 30). None of the women reported depressive symptoms during open label estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity. Women with past PMD who continued on estradiol and all control women remained asymptomatic. Importantly, women with past PMD and control women had similar hot-flush severity and plasma estradiol levels during placebo and, therefore, neither differences in hot-flushes (and the attendant sleep-disturbance) nor peripheral estradiol levels accounts for the differential response to estradiol withdrawal. In women with past PMD, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. These data also suggest that women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy. In collaboration with David Goldmans laboratory at NIAAA, we are currently investigating the effects of estradiol withdrawal on gene expression (RNA-seq) in lymphoblastoid cell lines (LCLs) obtained from women with past PMD and controls who had the presence and absence, respectively, of estradiol withdrawal-induced depressive symptoms confirmed in the clinical study. Finally, we will explore whether the estradiol withdrawal signal is mediated by ER alpha or beta (or both) by employing a selective ER beta agonist. These data could identify a promising new class of therapeutic agents that are safer and more acceptable than estrogen and potentially lack the side effects or withdrawal syndromes associated with traditional psychotropics. Additionally, it is possible that the selectivity of these compounds for estrogen receptor alpha and beta may identify the mechanisms of efficacy of estradiol on specific target symptoms.